Title

Author

Date of Award

12-2006

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Legacy Department

Bioengineering

Advisor

Vyavahare, Naren R

Abstract

Elastin is an important component of the extracellular matrix that endows cardiovascular tissue with the ability to extend and recoil repetitively. It has been shown that elastin may be vulnerable to enzymatic degradation and calcification in certain pathological cases. As a result, elastin degeneration may be associated with the failure of tissue-derived cardiovascular devices, such as bioprosthetic heart valves, as well as the development and progression of aortic aneurysms, a disease associated with progressive connective tissue degeneration of the arterial wall. Therefore, an elastin stabilizing agent may be beneficial for both applications. As such, our objectives for elastin stabilization are two-fold: (1) in the case of tissue-derived cardiovascular implants, to develop a tissue pretreatment targeting elastin stabilization that may significantly extend the clinical durability of such devices, and (2) to hinder the progression of aortic aneurysm formation by limiting elastin degradation with the delivery of therapeutic elastin stabilizing agents. For both of these applications, we propose to stabilize elastin using tannins, a class of naturally derived plant polyphenols known to interact with elastin. In studies presented here, we have confirmed that tannins bind to elastin, resulting in improved resistance to elastolytic degradation. This binding is effective within treated porcine aortic wall, as suggested by the preservation of elastin through in vitro and in vivo studies. Tannin-mediated elastin stabilization also correlated into a decreased propensity of aortic tissue to calcify in vivo. These data indicate that tannins may be used to improve the chemical fixation or pretreatment step used with tissue-derived cardiovascular implants, thus increasing the longevity of these devices. In addition, using an animal model to induce abdominal aortic aneurysm formation, we were able to show that elastin stabilization (via tannin treatment) may be effective in inhibiting aneurysm formation and progression. The potential use of tannins as a novel therapy for abdominal aortic aneurysms is significant, as the only current treatment for this potentially fatal pathology is surgical repair (bypass with a stent graft) or outright surgical replacement, options which possess substantial drawbacks.